Our goal in this research is to develop a safe, reversible method of menstrual suppression with a class of compounds called antiprogestins. Previously we showed that short-term systemic treatment with the Schering antiprogestin ZK 137 316 (ZK316) will suppress menstruation. We have now conducted a long-term study of cycling rhesus monkeys treated with ZK316. In this study, all of the animals exhibited normal pretreatment menstrual cycles (mean _ SE; 28.3 _ 1.4 days). Injection with ZK316 at 0.05 and 0.1 mg/kg for 100 days blocked menstruation and significantly extended the intermenstrual interval in all of the monkeys. Intermenstrual interval in the control, 0.05 and 0.1 groups were 28.1 _ 0.83, 131.1 _ 10.1 and 134 _ 8.7 days, respectively (P < 0.001). During the last 30 days of treatment, the monkeys in the control group expressed normal menstrual cycle patterns of estradiol (E2) and progesterone (P). In addition, all of the monkeys in the 0.05 mg/kg ZK316 grou p (n = 4) had normal follicular phase levels of E2 (including an E2 surge) and normal luteal phase levels of P. In this group, ZK316 suppressed menstruation despite a normal decline in luteal phase P at the end of the cycle. However, all of the monkeys in the 0.1 mg/kg group failed to develop a normal E2 surge (E2 levels rising above 200 pg/ml) or normal luteal phase levels of P (>1 ng/ml) during the last 30 days of treatment. Despite blockade of ovulation in this group, all of the monkeys showed normal nonsurge levels of E2 levels (~30-100 pg/ml). All ZK316-treated monkeys returned to normal cyclicity within 40 days and posttreatment cycle lengths were normal in all of the groups (29.8 _ 3.0 days). No untoward effects of treatment were detected in the monkeys during the study. In summary, we have now shown that long-term antiprogestin treatment will reversibly inhibit menstruation in rhesus monkeys.